Pregabalin sleep quality

Pregabalin sleep quality DEFAULT

Effects of Pregabalin in Patients with Hypnotic-Dependent Insomnia

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Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013383/

Background/Purpose:

Pregabalin is often administered for treatment of fibromyalgia (FM) at daily doses lower than approved by the US Food and Drug Administration (starting dose 150 mg; recommended dose 300–450 mg). The objective of this post-hoc analysis was to characterize pregabalin efficacy across a range of doses and set expectations regarding the incidence of adverse events (AEs) through the course of FM treatment.

Methods:

A hyperbolic Emax dose-response model using patient data pooled from 3 FM placebo-controlled trials examined the dose-response of pregabalin for pain (≥30% pain response), patient global impression of change (PGIC) and sleep quality. All patients had a diagnosis of FM based on the 1990 ACR criteria. After starting treatment, new incidences of AEs by study week were used to assess safety. Trials are identified by Pfizer study number (ClinicalTrials.gov identifier): 1008-105, A0081056 (NCT00645398), A0081077 (NCT00230776).

Results:

The likelihood of FM patients achieving ≥30% pain response incrementally increased from 27.5% (90% CI, 23.8–31.5%) with placebo to 31.5% (27.5–35.8%) at 150 mg/d, 33.0% (30.4–35.7%) at 300 mg/d, 33.7% (31.3–36.3%) at 450 mg/d and 34.2% (31.0–37.6%) at 600 mg/d. The likelihood of improvements in PGIC increased in a dose-dependent manner with higher pregabalin doses (Fig. 1). Incremental improvements in sleep quality also occurred with increasing doses (Fig. 2). It was not possible to estimate the value of Emax and ED50 parameters for sleep quality over the current dose range and therefore the upper plateau of the dose-response curve was not attained for this endpoint. The resulting curve appears linear, a finding not expected over a broader dose range or using data from different trials. Dizziness and somnolence were commonly reported AEs. New incidences of dizziness and somnolence were highest after 1 week of treatment and were considerably fewer subsequently, decreasing week by week for the same dose (Fig. 3).

Conclusion:

These data demonstrate the dose-response of pregabalin for pain, PGIC, and sleep, and highlight the incremental benefit of achieving the maximum recommended doses of 300–450 mg/d for treatment of FM. Common AEs are generally seen within 1 week of starting treatment, with few subsequent new reports for the same dose. This study was sponsored by Pfizer.                        

       

   

 


Disclosure:A. Clair, Pfizer, 1,Pfizer, 3; E. Whalen, Pfizer Inc, 1,Pfizer Inc, 3; N. Thomas, Pfizer Inc, 1,Pfizer Inc, 3; L. Pauer, Pfizer Inc, 1,Pfizer Inc, 3.

To cite this abstract in AMA style:

Clair A, Whalen E, Thomas N, Pauer L. Pregabalin Dose-Response for Sleep Quality and Pain Response in Fibromyalgia: A Post-Hoc Analysis of Three Randomized Trials [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/pregabalin-dose-response-for-sleep-quality-and-pain-response-in-fibromyalgia-a-post-hoc-analysis-of-three-randomized-trials/. Accessed October 16, 2021.

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Effects of pregabalin on sleep in generalized anxiety disorder

Abstract

Sleep disturbance is a cardinal symptom in both DSM-IV and ICD-10 criteria for generalized anxiety disorder (GAD). This review summarizes the results of clinical trials and pooled analyses that provide data on pregabalin's effect on sleep disturbance in patients diagnosed with GAD. The hypothesized mechanism of action of pregabalin is distinctly different from other anxiolytics. Pregabalin binds to a membrane α2δ subunit protein to inhibit release in excited central nervous system neurons of neurotransmitters implicated in pathological anxiety. Treatment with pregabalin has been found to be associated with significant improvement in GAD-related sleep disturbance across seven placebo-controlled clinical trials. Treatment with pregabalin is associated with improvement in all forms of insomnia and improvement in sleep has been found to be correlated with reduction in functional impairment and improvement in quality of life on subjective global measures. Results of a mediational analysis suggest that 53% of the effect of pregabalin on sleep disturbance was due to a direct effect and 47% was due to an indirect effect, mediated through prior reduction in anxiety symptom severity. In patients with GAD, improvement in sleep has been found to be associated with a reduction in daytime sleepiness. However, dose-related sedation is reported, typically in the first 2 wk of treatment, in approximately 10–30% of patients, depending on the dose used and the speed of titration. Insomnia is a common component of the clinical presentation of GAD and pregabalin appears to be an efficacious treatment for this often chronic and disabling symptom.

Anxiety, insomnia, pregabalin, sleep disturbance

Introduction

Generalized anxiety disorder (GAD) is a common disorder with a lifetime prevalence in the community estimated to range from 2.8 to 5.7% (Alonso & Lepine, 2007; Kessler et al.2005). Insomnia occurs even more frequently in the general population, with prevalence rates in the range of 5–15%, even when the diagnosis is restricted to severe complaints of disturbance in sleep onset or sleep maintenance that persist for >2 wk and are associated with significant impairment in functioning (Ohayon, 2002). Insomnia that presents as a symptomatic complaint, yet does not meet full diagnostic criteria, has been estimated to occur in approximately 25–30% of adults in the general population and has been associated with significant levels of occupational impairment (Kessler et al.2011; Ohayon, 2002).

GAD and insomnia frequently co-occur. This is partly attributable to the fact that sleep disturbance is a cardinal diagnostic criterion for GAD in both the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (Slade & Andrews, 2001). In fact, the symptom of insomnia has been reported to be the most frequent primary complaint among patients presenting with GAD in the primary care practice setting, with an incidence of 32.5% (Wittchen et al.2002). Full diagnostic co-morbidity between insomnia and GAD is also very common.

Insomnia and major depressive disorder (MDD) have a high level of co-morbidity; the presence of insomnia is associated with a significantly higher likelihood of having a GAD diagnosis when compared to patients who do not report insomnia (Breslau et al.1996; Johnson et al.2006; Taylor et al.2005). The results of several longitudinal studies indicate that insomnia, either as a symptom or a diagnosis, typically precedes the onset of MDD, frequently by >1 yr, with onset of insomnia associated with a 4-fold increased risk of developing a subsequent episode of MDD (Breslau et al.1996; Chang et al.1997; Eaton et al.1995; Johnson et al.2006; Weissman et al.1997).

In contrast, the onset of an anxiety disorder (most notably, GAD) has been reported to precede the onset of insomnia in the majority of cases (Johnson et al.2006; Ohayon & Roth, 2003). The occurrence of an anxiety disorder has also been reported to be associated with a 3- to 5-fold higher risk of developing subsequent insomnia (Breslau et al.1996; Chang et al.1997; Eaton et al.1995; Johnson et al.2006; Paffenbarger et al.1994; Weissman et al.1997).

The development of insomnia is associated with a significant impairment in functioning and quality of life (Breslau et al.1996; Hamilton et al.2007; LeBlanc et al.2007). Therefore, it is an important target for any effective treatment of GAD. Among patients entering treatment studies, in whom GAD is typically a chronic illness with a median duration >5 yr, moderate-to-severe levels of insomnia have developed in >75% of patients (Montgomery et al.2009).

Sleep disturbance in GAD

Individuals diagnosed with GAD report a range of subjective sleep complaints, including difficulty with sleep onset (in approximately 50%) and difficulty with sleep maintenance (in approximately 65%; Belanger et al.2004).

The few available studies of patients evaluated in sleep laboratories have found GAD to be characterized by significant reduction in sleep efficiency and total sleep time with delayed sleep onset and increased awakenings (including early morning awakening; Arriaga & Paiva, 1990; Fuller et al.1997; Papadimitriou et al.1988; Saletu-Zyhlarz et al.1997). Furthermore, polysomnography indicates that some individuals with GAD have significant reduction in slow-wave (stage 3/4) sleep (Monti & Monti, 2000) and rapid eye movement (REM) sleep abnormalities (e.g. reduced REM percentage and increased REM latency; Reynolds et al.1983).

The goal of this review is to summarize the effect of pregabalin on sleep disturbance in patients diagnosed with GAD.

Pregabalin pharmacology

Despite its name, pregabalin has no clinically relevant binding to any γ-aminobutyric acid (GABA) type A or type B receptors or transporters (Li et al.2011). Instead, pregabalin exhibits high affinity binding to the α2δ type 1 protein of a neuronal voltage-gated calcium channel. Pregabalin binding reduces the intracellular availability of calcium that is required for membrane fusion and release of neurotransmitter into the synaptic cleft, thus resulting in significant inhibition of the release of neurotransmitters implicated in pathological anxiety, such as glutamate and monoamine neurotransmitters (Coderre et al.2005; Cunningham et al.2004; Dooley et al.2000a, b; Li et al.2011; Maneuf et al.2001; Maneuf & McKnight, 2001).

Pregabalin's mechanism of action (MOA; reducing neuronal excitability) stands in contrast to the MOA of benzodiazepines, which act by enhancing inhibitory activity in the GABAergic receptor complex, the most widely distributed fast inhibitory neurotransmitter in the central nervous system (Kent et al.2002). The MOA of pregabalin also differs from the MOA of the selective serotonin reuptake inhibitor (SSRI) and serotonin–norepinephrine reuptake inhibitor (SNRI) antidepressants that have demonstrated anxiolytic activity and that appear to act via monoaminergic circuits that are hypothesized to underlie various anxiety-related symptoms and behaviours (Andrade, 2011; Martin et al.2010).

The MOA of pregabalin is associated with broad-spectrum efficacy across a range of clinical disorders, in which the final common pathway appears to be central sensitization (as in neuropathic pain and possibly fibromyalgia; Freeman et al.2008; Owen, 2007) or neuronal excitability (as in epilepsy and GAD; Hamandi & Sander, 2006; Kasper et al.2009) or some forms of insomnia associated with hyperarousal (Drake et al.2003).

The different MOAs among the three major classes of anxiolytics (pregabalin, benzodiazepines and SSRI/SNRI anxiolytics) are also associated with differences in the effect on sleep and sleep architecture, as well as the risk of daytime sedation as an adverse effect.

Effect of pregabalin on sleep architecture: data from a healthy volunteer population

Hindmarch et al. (2005a) conducted a randomized, double-blind, placebo-controlled evaluation of the effect of pregabalin and alprazolam vs. placebo on sleep. Before reviewing these data, it is important to note that the study was conducted in a normal control population and it is uncertain whether the results generalize to patients diagnosed with GAD. Compared to placebo, pregabalin significantly increased restorative stage 3/4 sleep, both as a proportion of the total sleep period and the duration of stage 4 sleep. In contrast, alprazolam significantly reduced slow-wave sleep when compared to placebo, which is consistent with findings from previous studies (Barbanoj et al.2005). Even though the study subjects were normal volunteers with no sleep complaints, treatment with pregabalin and alprazolam both resulted in significant increases in total sleep time and improvement in sleep efficiency. These results in normal volunteers are consistent with preclinical results in rodents, which have showed that pregabalin enhances slow-wave and non-REM sleep (Kubota et al.2001). In studies of clinical populations such as those with neuropathic pain, epilepsy, fibromyalgia and GAD (as summarized in the following section), treatment with pregabalin has also been found to significantly increase total sleep time and sleep efficiency (de Haas et al.2007; Roth et al.2010; Russell et al.2009; Sabatowski et al.2004; van Seventer et al.2006).

Efficacy in treating insomnia in patients with GAD: results from individual studies

The efficacy of pregabalin in treating symptoms of insomnia in patients with GAD has been established on the basis of results from seven previously reported randomized, double-blind, placebo-controlled, short-term trials (RCTs; Feltner et al.2003; Kasper et al.2009; Montgomery et al.2006, 2008; Pande et al.2003; Pohl et al.2005; Rickels et al.2005).

Across all seven individual RCTs, consistent improvement in insomnia on pregabalin treatment was demonstrated on the Hamilton Anxiety Rating Scale (HAMA) insomnia item (Fig. 1a), which rates the overall severity of sleep disturbance on a 5-point scale, ranging from 0 (not present) to 4 (very severe). Consistent improvement on pregabalin treatment was also demonstrated for each individual RCT on the three-item sleep disturbance factor of the Hamilton Depression Rating Scale (HAMD; Fig. 1b). The HAMD sleep disturbance factor rates early insomnia (difficulty falling asleep), middle insomnia (difficulty staying asleep or restless/disturbed sleep) and late insomnia (waking up too early) on a 3-point severity scale.

Fig. 1

Change in insomnia for individual short-term, placebo-controlled trials of pregabalin in generalized anxiety disorder [last observation carried forward (LOCF) end-point analysis]. (a) Hamilton Anxiety Rating Scale (HAMA) insomnia item change score; (b) Hamilton Rating Scale for Depression (HAMD) sleep disturbance factor change score. Pgb, Pregabalin; Loraz, lorazepam; Alpraz, alprazolam; Venla, venlafaxine. * p < 0.05 vs. placebo; ** p < 0.01 vs. placebo; *** p < 0.001 vs. placebo.

Fig. 1

Change in insomnia for individual short-term, placebo-controlled trials of pregabalin in generalized anxiety disorder [last observation carried forward (LOCF) end-point analysis]. (a) Hamilton Anxiety Rating Scale (HAMA) insomnia item change score; (b) Hamilton Rating Scale for Depression (HAMD) sleep disturbance factor change score. Pgb, Pregabalin; Loraz, lorazepam; Alpraz, alprazolam; Venla, venlafaxine. * p < 0.05 vs. placebo; ** p < 0.01 vs. placebo; *** p < 0.001 vs. placebo.

Two of the seven GAD trials concurrently evaluated the anxiolytic efficacy of pregabalin and venlafaxine, both the immediate-release formulation (Montgomery et al.2006) and the extended-release formulation, venlafaxine-XR (Kasper et al.2009). When compared to placebo, improvement on the HAMD sleep disturbance factor at the 6-wk end-point in the first study (Montgomery et al.2006) was significantly greater than placebo (−0.53) for fixed doses of 400 mg/d pregabalin (−1.26; p < 0.001) and for 600 mg/d pregabalin (−1.24; p < 0.001). The magnitude of improvement in the HAMD sleep disturbance factor was lower for the immediate-release formulation of venlafaxine when compared to placebo (−0.92; p < 0.05; Montgomery et al.2006).

Similar findings were obtained in an 8-wk, flexible-dose study that evaluated treatment with 300–600 mg/d pregabalin and 75–225 mg/d venlafaxine-XR (Kasper et al.2009). Compared to placebo (−0.58), treatment with pregabalin was associated with significant end-point improvement on the HAMD sleep disturbance factor (−0.98; p < 0.05), whereas end-point improvement was not observed vs. placebo for treatment with venlafaxine-XR (−0.43; not significant; Kasper et al.2009). In this same study, the effect of both drugs on insomnia was also assessed using a validated sleep outcome measure, the 12-item Medical Outcomes Study (MOS) Sleep Scale, which includes both a MOS-sleep disturbance factor and a MOS-sleep problems index (Hays et al.2005). As can be seen in Fig. 2a, b, treatment with pregabalin was associated with significant improvement in both MOS-sleep factors at week 4, week 8 and at last observation carried forward (LOCF) end-point, whereas significant improvement was not observed vs. placebo in patients treated with venlafaxine-XR.

Fig. 2

Least squares (LS) mean change from baseline in Medical Outcomes Study (MOS)-sleep factors. (a) MOS-sleep disturbance factor; (b) MOS-sleep problems index. * p < 0.05 vs. placebo; ** p < 0.001 vs. placebo.

Fig. 2

Least squares (LS) mean change from baseline in Medical Outcomes Study (MOS)-sleep factors. (a) MOS-sleep disturbance factor; (b) MOS-sleep problems index. * p < 0.05 vs. placebo; ** p < 0.001 vs. placebo.

Effect of pregabalin on HAMD insomnia factor scores

Symptomatic anxiety has been most frequently associated with high levels of arousal that interfere with the ability to fall asleep (early insomnia; Drake et al.2003). However, patients who meet criteria for GAD often present with insomnia that interferes with both sleep initiation and sleep maintenance. Pooled data from four treatment studies (Montgomery et al.2009) found that GAD patients most commonly reported ‘severe’ levels of early insomnia (28.7%), but 24.0% reported ‘severe’ difficulty staying asleep and 13.7% reported ‘severe’ early morning awakening, a symptom typically associated with MDD (Fig. 3). Even in this subgroup of patients with ‘severe’ insomnia, 4–6 wk treatment with pregabalin was associated with full symptomatic remission of early, middle and late insomnia in >50% of patients (Fig. 4).

Fig. 3

Frequency of insomnia complaints rated as ‘severe’ by patients with generalized anxiety disorder: pooled results from four randomized clinical trials.

Fig. 3

Frequency of insomnia complaints rated as ‘severe’ by patients with generalized anxiety disorder: pooled results from four randomized clinical trials.

Fig. 4

Remission rates for severe insomnia (baseline Hamilton Rating Scale for Depression insomnia factor score >3) during 4–6 wk double-blind treatment with pregabalin (Pgb) or placebo (n=1354).

Fig. 4

Remission rates for severe insomnia (baseline Hamilton Rating Scale for Depression insomnia factor score >3) during 4–6 wk double-blind treatment with pregabalin (Pgb) or placebo (n=1354).

GAD presenting with high levels of insomnia

A pooled analysis of six double-blind, placebo-controlled clinical trials provides the largest dataset to examine the efficacy of pregabalin and benzodiazepines in treating patients with GAD presenting with moderate-to-severe levels of insomnia (Montgomery et al.2009). A high (moderate-to-severe) level of insomnia was operationally defined as a score of ⩾4 (of a maximum of 6) on the three-item HAMD sleep disturbance factor. Of a combined sample of 1854 patients, 1002 (54.0%) met criteria for moderate-to-severe insomnia. Treatment with pregabalin in the dosage range of 300–600 mg/d was associated with significant improvement in insomnia in this moderate-to-severe subgroup (Fig. 5). Onset of significant improvement in insomnia occurred by week 1 in both the pregabalin and the benzodiazepine treatment groups. End-point improvement in insomnia was similar after 4–6 wk treatment with both pregabalin and benzodiazepines.

Fig. 5

Efficacy of short-term treatment with pregabalin (Pgb) and benzodiazepines in improving sleep disturbance in patients with generalized anxiety disorder presenting with moderate-to-severe insomnia (high subgroup) or mild-to-no insomnia (low subgroup). Loraz/Alpraz, lorazepam and alprazolam. Hamilton Rating Scale for Depression (HAMD) sleep disturbance factor is the sum of items 4 (early), 5 (middle) and 6 (late) insomnia. p value vs. placebo is based on analysis of covariance. ** p < 0.01; *** p < 0.001. Figure reproduced with permission (Montgomery et al. 2009).

Fig. 5

Efficacy of short-term treatment with pregabalin (Pgb) and benzodiazepines in improving sleep disturbance in patients with generalized anxiety disorder presenting with moderate-to-severe insomnia (high subgroup) or mild-to-no insomnia (low subgroup). Loraz/Alpraz, lorazepam and alprazolam. Hamilton Rating Scale for Depression (HAMD) sleep disturbance factor is the sum of items 4 (early), 5 (middle) and 6 (late) insomnia. p value vs. placebo is based on analysis of covariance. ** p < 0.01; *** p < 0.001. Figure reproduced with permission (Montgomery et al. 2009).

Insomnia and quality of life/functioning

In the study by Kasper et al. (2009) summarized previously, the MOS-sleep problems index identified 64.5% of patients with GAD as meeting criteria for insomnia (using the validated criteria score of ⩾45; Hays et al.2005). The HAMA total score (with the insomnia item not included) was similar at baseline in the insomnia vs. non-insomnia subgroups (25.7 vs. 25.0). Despite similar levels of anxiety severity, the presence of insomnia was associated with significantly greater impairment in quality of life, as measured by the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) total score (45.3 vs. 53.6; p < 0.0001; Mychaskiw et al.2009). Similarly, the mean scores at baseline on the Sheehan Disability Scale were significantly higher (greater impairment) in the insomnia vs. non-insomnia subgroup (17.5 vs. 14.3; p < 0.0001; Mychaskiw et al.2009). A Spearman correlational analysis found that end-point improvement on the MOS-sleep problems index was associated with significant improvement in the Sheehan Disability Scale (r = 0.46; p < 0.0001) and in the Q-LES-Q scale (r = − 0.48; p < 0.0001; an inverse correlation since a higher Q-LES-Q score is associated with improved quality of life).

Effect of pregabalin on sleep in GAD: results of a mediational analysis

The study by Kasper et al. (2009) also provided an opportunity to address the mechanistic question as to whether improvement in sleep observed in patients with GAD treated with pregabalin was a direct effect on the GAD symptom of insomnia or an indirect consequence of first reducing other anxiety symptoms, which then enhanced a patient's ability to initiate and maintain sleep. A mediational analysis was performed in which a series of multivariate regression models are simultaneously fit to the average of the HAMA total score and MOS-sleep disturbance subscale (Kline, 2005; MacKinnon, 2008). The direct and indirect effects on sleep disturbance are then estimated as the percentage of total effect that was explained by each path.

The results of this mediational analysis (Bollu et al.2010) found that 53% of the effect of pregabalin on sleep disturbance was due to a direct effect on the GAD symptom of insomnia and 47% was due to an indirect effect, mediated through prior reduction in anxiety symptom severity (Fig. 6). The results of a mediational analysis of pain-related sleep interference in patients diagnosed with fibromyalgia (Russell et al.2009) found similar improvement in sleep, which was attributable both to a direct effect of pregabalin in reducing insomnia and to an indirect effect resulting from improvement in pain that was interfering with sleep. Pregabalin has been found to improve sleep across a wide range of disorders, including neuropathic pain, epilepsy and fibromyalgia (de Haas et al.2007; Roth et al.2010; Russell et al.2009; Sabatowski et al.2004; van Seventer et al.2006). The degree of sleep improvement may not be solely correlated with reduction in pain or improvement in epilepsy. These findings are consistent with the hypothesis that pregabalin could have a primary effect of improving sleep that is independent of its anxiolytic or anti-nociceptive effect. However, it is important to remember that GAD is the only psychiatric indication for which pregabalin is currently approved in the EU.

Fig. 6

Direct and indirect effects of pregabalin in improving sleep: results of a mediational analysis. HAMA, Hamilton Anxiety Rating Scale; MOS, Medical Outcomes Study; Venla-XR, venlafaxine-XR.

Fig. 6

Direct and indirect effects of pregabalin in improving sleep: results of a mediational analysis. HAMA, Hamilton Anxiety Rating Scale; MOS, Medical Outcomes Study; Venla-XR, venlafaxine-XR.

GAD and insomnia in the elderly: effect of pregabalin

One population that is especially at risk for insomnia is the elderly patient with GAD. The base rate of insomnia complaints in the non-anxious elderly is notably higher than it is in young adults, with a prevalence of 30–50% (Foley et al.1999; Ohayon, 2002). The efficacy of pregabalin in treating GAD in the elderly was evaluated in a double-blind, placebo-controlled trial (Montgomery et al.2008). Elderly patients were treated with flexible daily doses of pregabalin in the range of 150–600 mg, with a mean daily dose of 270 mg. Initial dose titration in this elderly sample was slower than in previous adult studies, with pregabalin treatment initiated at 50 mg/d, followed by an increase to 100 mg/d on day 3 and 150 mg/d on day 5.

At baseline, 65.7% of patients met criteria for moderate-to-severe insomnia (HAMD sleep disturbance score ⩾3 of a maximum score of 6); with 57.9% reporting severe early insomnia, 40.4% severe middle insomnia and 26.4% severe early morning awakening. Treatment with pregabalin significantly reduced the HAMA total score compared to placebo and significantly improved insomnia symptoms in the moderate-to-severe subgroup, with 64.2% achieving insomnia responder status on a LOCF end-point analysis (vs. 44.1% on placebo; p < 0.05). Furthermore, complete remission of insomnia symptoms was achieved by 43.3% of patients with severe early insomnia, 40.4% of patients with severe middle insomnia and 42.2% of patients with severe late insomnia.

Safety and tolerability

Overall, treatment with pregabalin is well tolerated; many of the most frequent adverse events (e.g. somnolence, dizziness) are mild-to-moderate in intensity and are limited to the first 2–3 wk treatment (Montgomery, 2006; Montgomery et al.2008). The efficacy of pregabalin in improving insomnia in patients diagnosed with GAD must be weighed against the potential for causing daytime sedation. There are two sources of information that provide data on the incidence of somnolence during treatment with pregabalin. The first dataset consists of phase II/III clinical trials of pregabalin in GAD. The incidence of somnolence in pooled data from these studies is summarized in Fig. 7a (Montgomery et al.2009). As can be seen, there is a modest dose-related increase in somnolence across the dosing range of 150–600 mg/d. In patients with GAD presenting with moderate-to-severe levels of insomnia, treatment with pregabalin, even at the 600 mg/d dose, is associated with a lower incidence of insomnia than treatment with benzodiazepines (31.5% vs. 54.2%; Montgomery et al.2009). It is important to note that all of these phase II/III studies were designed as fixed-dose clinical trials with rapid titration (within 7 d) to the assigned dose. In these fixed-dose studies, the median time to onset of somnolence was 1–3 d (depending on the speed of titration) and the median time to resolution of somnolence was 10–24 d, with longer persistence of somnolence occurring at higher doses.

Fig. 7

Incidence of somnolence: pooled data from short-term treatment studies. (a) Fixed-dose studies with forced titration; (b) flexible-dose studies. Pgb, Pregabalin.

Fig. 7

Incidence of somnolence: pooled data from short-term treatment studies. (a) Fixed-dose studies with forced titration; (b) flexible-dose studies. Pgb, Pregabalin.

The second dataset, which is more generalizable to actual clinical practice, consists of two flexible-dose studies that permitted titration, based on clinical response, to the optimal dose of pregabalin. In the first study (Kasper et al.2009), the incidence of somnolence was notably lower (9.1%) than in the rapid titration fixed-dose studies (Fig. 7b). In the second study, conducted in the elderly (Montgomery et al.2010), the incidence of somnolence was similar in both pregabalin- and placebo-treated patients (10.6% vs. 9.4%; Fig. 7b).

In addition to evaluating somnolence as a patient-reported adverse event, the flexible-dose study used the MOS-sleep scale to measure the effect of pregabalin treatment on the daytime sleepiness factor. As can be seen in Fig. 8, treatment with pregabalin resulted in improvement on the MOS daytime sleepiness factor that was non-significantly greater than the improvement observed on placebo (Donevan et al.2010). A Spearman analysis found that end-point improvement on pregabalin in the MOS daytime sleepiness factor score was correlated at a trend-significant level with improvement in the HAMD sleep disturbance factor score (r = 0.18; p = 0.065). This suggests that improvement in daytime sleepiness/fatigue may be a secondary benefit of treatment with pregabalin that is separate from the occurrence of somnolence as an early-onset adverse event.

Fig. 8

Least squares (LS) mean change from baseline in Medical Outcomes Study (MOS) daytime sleepiness factor. Data not significant.

Fig. 8

Least squares (LS) mean change from baseline in Medical Outcomes Study (MOS) daytime sleepiness factor. Data not significant.

In addition to daytime somnolence, treatment of anxiety with benzodiazepines is associated with significant impairment in both cognitive and psychomotor function (Lister et al.1988). Furthermore, the attentional and psychomotor effects of benzodiazepines has been linked to a 1.5- to 2-fold increased risk of being in an automobile accident (Barbone et al.1998; Hemmelgarn et al.1997) and a >5-fold increased risk of being in a serious accident requiring hospitalization (Neutel, 1995). The effect of pregabalin and alprazolam on cognitive, psychomotor and driving performance has been evaluated in a cohort of non-anxious subjects using a battery of psychometric tests (Hindmarch et al.2005b). Treatment with alprazolam was associated with significant impairment compared to placebo in all attentional, cognitive and reaction time tests, which included brake reaction time in an on-the-road vehicle. In contrast, treatment with pregabalin was associated with improvement relative to placebo in brake reaction time and notably less impairment compared to alprazolam in daytime sedation and other measures of attention and cognitive functioning (Hindmarch et al.2005b). Impairments were observed on pregabalin in some tests (e.g. critical flicker fusion, tracking accuracy in a compensatory tracking task), but the impairments were modest, transient and significantly lower than the effects observed on alprazolam.

The results of this study suggest that pregabalin may have a more favourable cognitive and psychomotor safety profile compared to alprazolam. However, the magnitude of the cognitive and psychomotor effects can only be fully evaluated in a clinical population of patients diagnosed with GAD. The only available data we are aware of come from a RCT of pregabalin for the treatment of GAD in elderly patients (Montgomery et al.2008). Because the elderly are particularly sensitive to adverse cognitive effects of benzodiazepines, the study included standardized cognitive assessments (e.g. Digit Symbol Substitution Test, set test). Treatment with pregabalin was not associated with cognitive impairment when compared to placebo on any of the cognitive test battery (Baldinetti et al.2010).

A final safety concern regarding treatment with various classes of anxiolytics is the potential for abuse, dependence and symptoms of withdrawal when discontinuing long-term therapy. Compared to benzodiazepines, pregabalin appears to have a lower risk of abuse and dependence (Feltner et al.2008; Montgomery & Kasper, 2010). However, occasional cases of abuse have been reported and therefore caution should be exercised in prescribing pregabalin to patients with a history of substance abuse or alcoholism.

Conclusions

Insomnia is one of the most frequent and disabling symptoms of GAD. As such, it is an important target for any effective therapy. Pregabalin belongs to a relatively new class of anxiolytics whose MOA, reducing neuronal excitability, stands in contrast to the anxiolytic mechanism of benzodiazepines, which target inhibitory activity in the benzodiazepine-GABAergic receptor complex. As this review has shown, treatment with pregabalin is associated with improvement in early, middle and late forms of insomnia, with improvement in sleep among patients with GAD resulting in reduction in functional impairment and improvement in quality of life. Overall, treatment with pregabalin is well tolerated and many of the most common adverse events are mild to moderate in intensity and limited to the first 2–3 wk treatment. Although sedation may occur as an adverse event in some patients, the incidence is lower compared to benzodiazepines. Pregabalin is a valuable treatment option for patients with GAD who present with insomnia.

Acknowledgements

The authors thank Birol Emir (Pfizer Inc) for help with the statistical analyses. Medical writing support was provided by Dr Edward Schweizer, owner of Paladin Consulting Group Inc, and funded by Pfizer Inc. Editorial support to prepare this manuscript for submission was provided by Lorna Forse, PhD, of UBC Scientific Solutions and funded by Pfizer Inc. The authors are entirely responsible for the scientific content of the paper.

Statement of Interest

Dr Edith Holsboer-Traschler has received funding from Bristol-Myers Squibb, Eli Lilly SA Switzerland, GlaxoSmithKline AG, Servier (Switzerland) SA, Vivor SA and Zeller Medical; has received honoraria or consultancy fees from Eli Lilly SA Switzerland, Lundbeck, and Pfizer AG; and holds positions on the advisory boards of Eli Lilly SA Switzerland, Lundbeck, and Pfizer AG. Dr Rita Prieto is a full-time employee of Pfizer SLU.

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Sours: https://academic.oup.com/ijnp/article/16/4/925/792078
10 Questions about GABAPENTIN (Neurontin) for pain: uses, dosages, and risks

Pregabalin Benefits Pain Control, Sleep, Quality of Life, in Patients with Fibromyalgia

Patients with fibromyalgia have access to a limited number of therapeutic options. One of 3 drugs approved for patients with fibromyalgia, pregabalin is an anticonvulsant and α-2-Δ subunit receptor ligand that has shown clinically meaningful benefits across multiple fibromyalgia symptom domains.

“Pregabalin therapy in patients with fibromyalgia is modestly effective in terms of response, but a good number of patients are able to achieve meaningful benefit in terms of pain control, improvement of sleep, functioning, and quality of life,” Santosh Bhusal, MD, Division of Rheumatol­ogy, Metrohealth Medical Center, Cleveland, OH, and colleagues explained. “Pregabalin is cost saving to the society, especially if used at dosages ≥450 mg [a] day.”

Seeking to highlight the clinical utility of pregabalin in the management of fibromyalgia, the study authors conducted a review on the efficacy, safety, and cost-effectiveness of the drug.

Effects of Pregabalin on Pain, Sleep, and Quality of Life

As part of their review, the study authors discuss the mechanism of action of the drug as well as its pharmacokinetics. Taking a closer look at the clinical utility of pregabalin, they note that the drug does not only show benefits in pain management, but can also be used for sleep and quality of life.

Numerous randomized trials, including 2 meta-analyses, demonstrate the efficacy of pregabalin in the treatment of fibromyalgia pain, and were studied by the authors for the purpose of this review. Of note, one double-blind trial of 529 patients randomized to receive 150 mg, 300 mg, or 450 mg of pregabalin or placebo for 8 weeks resulted in significant pain improvement in patients receiving pregabalin 450 mg, compared with control. This improvement in pain was based on reduction of end point mean pain scores on weeks 1 to 7, and reports of >50% pain improvement from baseline (28.9% pregabalin vs 13.2% placebo; P = .003).

With regard to treatment of sleep disturbance, the authors were intrigued by pregabalin’s enhancement of slow-wave sleep. In a double-blind study of 12 healthy volunteers, patients treated with pregabalin 450 mg daily had higher proportions of stage 3 and 4 delta wave sleep compared with counterparts taking alprazolam and placebo. Pregabalin use was also linked to fewer awakenings of longer than a 1-minute duration. Another analysis of 2 randomized trials demonstrated that patients with fibromyalgia taking pregabalin had statistically significant improvements in sleep quality diary and medical outcome sleep study, with the difference with placebo going beyond the thresholds for clinical meaningfulness; results were reportedly more consistent at doses ≥450 mg a day.

Significant improvements have been noted in results of the fibromyalgia impact questionnaire (FIQ) with pregabalin doses of 450 mg and 600 mg daily, compared with placebo in a randomized trial. Another study evaluating pregabalin 450 mg daily also demonstrated noteworthy improvement in FIQ results compared with placebo. Dr Bhusal and colleagues noted that studies surrounding the SF-36 health survey—the other most commonly used measure for function and quality of life other than FIQ—yielded diverse results that were inconsistent across different studies.

Safety and Accessibility of Pregabalin

When looking at data evaluating the safety and accessibility of pregabalin, Dr Bhusal and colleagues observed that the rate of discontinuation for pregabalin is low, and although side effects are common with the drug, they do not interfere with functions of daily life.

According to the authors, randomized trials have indicated that approximately 80% to 90% of patients taking pregabalin had treatment-emergent adverse events, compared with approximately 70% to 75% of patients taking placebo. Dizziness and somnolence were the most common side effects reported.

Although weight gain is a less common side effect, it has been shown to lead drug discontinuation. In fact, Dr Bhusal and colleagues state that the incidence of weight gain has been shown to be as high as 18% to 26% annually in some long-term studies.

Other than these side effects, rare adverse events that have led to discontinuation of pregabalin therapy include chest pain, abnormal liver function tests, and suicidal ideation. Causal association of these events is hard to determine, they noted however, because they occur only once or twice per randomized trial and were not linked to pregabalin use.

Based on the information in pharmacoeconomic studies, the authors assert that pregabalin is cost-effective. According to a Markov model assessing cost-effectiveness of pregabalin in the United States, total and indirect costs for patients taking the drug at 300-mg and 450-mg doses daily were lower compared with placebo at 12 weeks; outpatient visit and medication costs, however, were slightly higher, Dr Bhusal and colleagues noted. Both dosages elicited more total, direct, and indirect cost-savings than placebo at 1 year. Pregabalin was also found to be more cost-effective than duloxetine, gabapentin, and milnacipran. Long-term pregabalin use in patients with fibromyalgia—especially at doses ≥450 mg a day—is cost-effective and comparable to other drugs used in this patient population, the study authors suggested.

“Until the availability of better drugs in the future, pregabalin is well suited to serve as one of the ‘anchor drugs’ in fibromyalgia,” Dr Bhusal and colleagues concluded.




Reference

  • Bhusal S, Diomampo S, Magrey MN. Clinical utility, safety, and efficacy of pregabalin in the treatment of fibromyalgia. Drug Healthc Patient Saf. 2016;8:13-23.
Sours: http://www.valuebasedrheumatology.com/vbcr-issues/2016/april-2016-vol-5-no-2/26643-pregabalin-benefits-pain-control

Sleep quality pregabalin

Pregabalin beneficial effects on sleep quality or health-related quality of life are poorly correlated with reduction on pain intensity after an 8-week treatment course

Background: Pregabalin (PGB) has been shown to improve sleep quality and health-related quality of life (HRQoL) as well as pain intensity in patients with neuropathic pain.

Objective: The objective of the study was to explore the magnitude of the correlations between changes in pain intensity, sleep quality, and HRQoL after PGB treatment.

Methods: One hundred thirty-eight patients with neuropathic pain of any origin and without an adequate response to analgesics received an 8-week treatment course of PGB in an open-label fashion. Pain intensity, sleep quality, and HRQoL outcomes were evaluated at baseline and at week 8 by means of an 11-point (0-10) numerical rating scale (NRS), the Pittsburgh Sleep Quality Index (PSQI), and the EuroQol health-state visuoanalogic scale (EQ-5D VAS) score, respectively.

Results: At week 8, mean PGB dose was 166.7 ± 7.8 mg/d. Pain intensity NRS score, PSQI total score, and EQ-5D VAS score were improved by 66.5% ± 1.9%, 40.0% ± 3.6%, and 26.4% ± 4.7% (all P < 0.01), respectively. Correlations between percent change from baseline in pain NRS score and PSQI total score or EQ-5D VAS scores were r = 0.36 (P < 0.01, R = 0.11) and r = -0.20 (P < 0.02, R = 0.05), respectively. A multivariate logistic regression analysis disclosed that PSQI score change below the median (ie, a better outcome) was related to higher EQ-5D VAS score change (odds ratio, 2.15; 95% confidence interval, 1.09-4.25), whereas pain intensity NRS score change below the median was not (odds ratio, 1.58; 95% confidence interval,0.78-3.23).

Conclusions: In our study, PGB-related improvements in sleep quality and HRQoL were marginally related to reductions in pain intensity in patients with neuropathic pain. Improvement in sleep quality was a significant predictor of better HRQoL, whereas pain intensity reduction was not.

Sours: https://pubmed.ncbi.nlm.nih.gov/22156921/
10 Questions about GABAPENTIN (Neurontin) for pain: uses, dosages, and risks

Distance and from such a perspective, could hardly hold back the impulse of flesh. The most interesting thing is that for some reason it also turned me on. After all, do not be jealous of a young kid, especially on a nudist beach. And if Irka likes it, let her look, it will not lose me.

Now discussing:

And it's good that I put on sandals with heels, they slim my legs. The mood improved, even my gait became somehow lighter, more sensual. I came to the bus stop. The trolleybus, it seems, just left and I was here alone.



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